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As part of the federal government’s National Institutes of Health (NIH), the National Eye Institute’s mission is to “conduct and support research, training, health information dissemination, and other programs with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of the blind.”

NEI-funded research points to novel therapies for dry eye

Recent strides toward understanding dry eye are leading to better and longer-lasting therapies for the millions of people in the U.S. who are affected by the condition.

Current therapies for dry eye provide symptomatic relief: steroids control inflammation, antibiotics counter infection, and artificial tears replenish moisture. But such approaches give only short-term relief for some people and require frequent reapplication. They also fail to address the underlying causes of dry eye.

The latest research funded by the National Eye Institute, part of the National Institutes of Health, suggests multiple factors contribute to dry eye, said George McKie, D.V.M., Ph.D., corneal diseases program director at NEI. “Scientists are discovering how the tear film that coats the eye maintains homeostasis, or equilibrium, of its three main layers.” The outer lipid layer keeps tears from evaporating too quickly and helps them cling to the eye’s surface. The middle aqueous layer contains mostly water, proteins and mucins, which nourish the cornea and flush away toxins and foreign bodies. The aqueous layer contains the bulk of basal tears, the type of tears that continuously moisten the eye. The innermost mucin layer inhibits microbial growth and binds water from the aqueous layer to ensure that the eye remains wet.

One novel therapy undergoing testing in clinical trials is a synthetic form of lacritin, a protein that stimulates basal tear production. More than two decades ago, NEI-funded researcher Gordon Laurie, Ph.D., a cell biologist at the University of Virginia, set out to identify a naturally produced eye substance to combat dry eye. At the time, dry eye research focused on inflammation. “Our goal was to find out what’s going on before the inflammation starts,” he said.

With NEI funding, Laurie and his team screened eye proteins for regulators of basal tearing. “It was like looking for a needle in a haystack,” Laurie noted. “Our tears contain many components, including 1,500 proteins. Identifying the key substance that stimulates tear production was a hard and slow process.” With time—and serendipity—they homed in on lacritin, which flows from the lacrimal gland onto the eye’s surface. It’s not entirely understood how lacritin stimulates basal tear production. Some data suggest it increases the sensitivity of nerves responsible for sensing dryness. Lacritin also appears to counter inflammatory factors called cytokines and activates autophagy, an intracellular process that removes damaged proteins to maintain overall cell health.

Studies show that deficient lacritin levels disrupt homeostasis, Laurie added. In animal studies, Laurie and his colleagues confirmed that a single dose of lacritin elevates basal tearing and that the benefits of daily dosing last at least one week after therapy stops.

An industry-sponsored, 27-site clinical trial is underway to investigate the use of synthetic lacritin in people with dry eye associated with the immune disorder Sjogren’s syndrome. Results are expected in early 2018. In the meantime, Laurie is developing a clinical test for lacritin deficiency to identify people who are candidates for replacement therapy.

Hiramitsu Hirata, Ph.D., of Weill Cornell Medicine, New York, and others are exploring factors that influence the ability of corneal nerves to sense basal tear evaporation. In a healthy eye, only one-tenth of a degree of cooling from evaporation is needed to activate corneal nerves, which in turn triggers basal tearing. But in dry eye, such cooling fails to trigger a response, spurring scientists to develop topical corneal nerve stimulators to increase nerve sensitivity to drying. And since corneal nerve number, length, and function are substantially diminished in dry eye, a goal of other NEI-funded researchers is to promote the regrowth of corneal nerves.

Meanwhile, a team at Stanford University, led by Daniel Palanker, Ph.D., has developed an implantable device that electrically stimulates the lacrimal gland to produce tears. In addition, it stimulates the nerves linking the brain and sensory neurons in eye, further prompting the lacrimal gland to produce tears. More recently, the team has been able to finetune the content of the tears by stimulating other glands around the eye. Their results produce tears that contain not only water, but lipids and mucins to more closely resemble the consistency of naturally-occurring basal tears.

Defining the molecular composition of the tear lipid layer is another area of research that NEI is funding. Ben Glasgow, M.D., at the University of California, Los Angeles, is studying the structure and function of lipid binding proteins in tears. Understanding the factors that stabilize the tear lipid layer could lead to therapies that reduce tear evaporation.

Stem cell therapy to repair the lacrimal glands is yet another area of intense investigation. Although at an early phase of development, such an approach could use a patient’s own cells to rebuild or replace the lacrimal glands, providing a possible long-term solution to dry eye.

Finally, an NEI-funded study is investigating the benefits of taking oral omega-3 fatty acids for dry eye. Several over-the-counter dietary supplements containing omega-3s are already available; however, claims about their efficacy are based on limited, small studies. These studies lack consistency in terms of the type and dose of omega-3 therapy used, explained Penny Asbell, M.D., professor of ophthalmology and director of the Cornea Service and the Refractive Surgery Center at Icahn School of Medicine at Mount Sinai, New York. Asbell leads the NEI-funded clinical trial, Dry Eye Assessment and Management Study (DREAM), the first large, independent, multisite investigation of omega-3s for dry eye. “In addition to evaluating the role of omega-3s in the outer, oily layer of tears, we expect to gain insights about the role of inflammation in dry eye. We hope to determine whether there are inflammatory biomarkers for dry eye.”

NEI leads the federal government’s research on the visual system and eye diseases. NEI supports basic and clinical science programs to develop sight-saving treatments and address special needs of people with vision loss. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.